Project Summary/Abstract Tobacco and alcohol use and genetic susceptibility are major risk factors for squamous cell carcinoma of the head and neck (SCCHN). Identification of susceptible individuals can effectively prevent this disease by avoiding tobacco and alcohol use. Tobacco carcinogens cause a variety of DNA damage in the target cells, which may lead to uncontrolled cell growth, but the cells evolve to have the mechanism of programmed cell death or apoptosis that helps eliminate cells with excessive damage to DNA and thus reduce risk of cancer. There are at least two known apoptotic pathways, intrinsic and extrinsic, that lead to cell death in response to excessive DNA damage. Many genes participate in these two apoptotic pathways, and there is an established flow cytometry method to detect the apoptosis phenotype. In this new grant application, we propose to perform the phenotypic apoptosis and genotyping assays in 600 newly recruited cases and 600 controls and to perform genotyping assays with stored DNA samples from previously recruited 1,000 SCCHN cases and 1,000 controls. For the genotyping, we propose to focus on the common, possibly functional single nucleotide polymorphisms (SNPs) that either cause amino acid changes or sequence variation in the regulatory regions that may alter gene expression or are reportedly associated with risk of smoking-related cancers. A total of 88 possibly functional SNPs in 45 apoptosis-related genes will be genotyped by the Taqman genotyping method using genomic DNA from 1,600 SCCHN cases (600 prospective and 1,000 retrospective) and 1,600 cancer- free controls (also 600 prospective and 1,000 retrospective). Our specific aims are: AIM 1: To determine the association between the apoptotic phenotype of lymphocytes and risk of SCCHN in 600 prospectively identified cases and 600 hospital-based controls frequency matched by age, sex, ethnicity/race and residence. We will test the hypothesis that lower levels of apoptotic capacity are associated with increased risk of SCCHN. AIM 2: To determine the functional relevance of selected common variants in apoptotic pathways in the 600 cases and 600 controls by identifying genotypes that predict the phenotype. We will test the hypothesis that possibly functional genetic variants of selected apoptotic genes have an effect on the apoptotic phenotype. AIM 3: To determine the association between common variant genotypes of the selected apoptosis-related genes and risk of SCCHN. We will test the hypothesis that adverse genotypes of selected apoptosis-related genes are associated with increased risk of SCCHN. This proposed association study is highly hypothesis-driven, expanding our preliminary data on the findings of a novel p53-PHB-PIG3 apoptosis mechanism. This study will identify genetic factors that predict the apoptotic phenotype and risk of SCCHN and thus will advance our knowledge in the etiology of SCCHN. The long-term goal of this study is to identify effective biomarkers for risk assessment and to identify at-risk individuals who can be targeted for primary prevention and early detection of SCCHN in the general population. Project Narrative This proposed study is to investigate the roles of genetic factors, as well as their interactions with tobacco and alcohol use, in the etiology of squamous cell carcinomas of the oral cavity, pharynx, and larynx (SCCHN), expanding our findings of a novel apoptosis mechanism that has not been described before. Therefore, this study will help understand the underlying mechanisms of the correlation between apoptosis genotypes and phenotypes to be measured and the roles they may play in the etiology of SCCHN. The long- term goal of this study is to identify effective biomarkers that can be used to identify at-risk individuals who will be targeted for primary prevention and early detection of SCCHN in the general population.